Benzocycloheptenones and derivatives



United States Patent 3,169,656 BENZOCYCLOHEP'I'ENONES AND DERIVATIVES Eohn Krapcho, Somerset, NJ., assignor to Olin Mathreson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed May 28, 1%2, Ser. No. 19718 8 Claims. (Cl. Zed-Sill) This invention relates to benzocycloheptenones and derivatives. More particularly, the invention relates to benzocycloheptenones represented by the structural formula R=N-lower alkylenefi) (I? (ll-lower alkyl and to their 6, 7, 8, Q-tetrahydro derivatives.

The symbol R=N in the above formula represents a basic nitrogen-containing radical of less than 12 carbon atoms. This includes the amino group, monoand disubstituted amino groups such as lower alkylamino, e.g. methylarnino, ethylamino, propylamino, isopropylamino and the like; di-lower alkylamino, e.g. dimethylamino, diethylamino and the like; hydroxy-lower alkylarnino, e.g. hydroxyethylamino; di-(hydroxy-lower alkyD-amino, e.g. dihydroxyethylamino; pheny1(lower alkyl)amino, e.g. benzlamino, phenethylamino and the like; N-(lower alkyl) N-(phenyl[lower alkyl])amino, e.g. N-methyl-N-benzylamino and the like. The basic-nitrogen containing radical may also take the form of a 5- to 6-membered monocyclic nitrogen heterocyclic which also may be substituted, in all containing less than 12 carbon atoms. Such heterocyclic radicals include, for example, nitrogen, oxygen and/or sulfur containing hetrocyclics as, piperidino, (lower alkyl)piperidino, di-(lower alkyDpiperidino, (lower alkoxy)piperidino, pyrrolidino, (lower alkyl) pyrrolidino, di(lower alkyl)pyrrolidino, (lower alkoxy) pyrrolidino, morpholine, (lower alkyl)morpholino, di(lower alkyl)morpholino, (lower alkoxy)morpholino, thiamorpholino, (lower aIkyDthiamorpholino, di(lower alky1)thiamorpholino, (lower alkoxy)thiamorpholino, piperazino, (lower alkyl)piperazino, di(lower alkyl)piperazino, (lower alkoxy) piperazino, hydroxyalkylpiperazino, etc. Attachment of the heterocyclic ring to the lower alkylene group may be through any ring element. The 2, 3- and 4-pyridyl radicals are also included.

The terms lower alkyl and lower alkylene refer to both straight and branched chain saturated hydrocarbon radicals of less than 8 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and methylene, ethylene and propylene, respectively.

Particularly preferred are those compounds of Formula I wherein all lower alkoxy groups are methoxy groups and R=N is a lower alkylamino group especially isopropylamino or a di-lower alkylamino group, especially dimethylamino. Preferably the lower alkylene chain has 2 carbon atoms.

The compounds of Formula I form acid addition salts and quaternary salts which are also within the scope of the invention. The bases form acid addition salts with pharmaceutically acceptable quaternizing agents such as inorganic acids, e.g. all four hydrohalic acids, but preferably hydrochloric and hydrobromic acids, other mineral acids such as nitric, sulfuric, phosphoric and the like, and organic acids such as oxalic, tartaric, citric, acetic, succinic, benzoic, salicyclic, ascorbic, mandelic, malic, methanesulfonic, benzenesulfonic, camphorsulfonic, etc.

Quaternary salts are formed with pharmaceutically acceptable quaternizing agents such as alkyl halides, preferably lower alkyl halides, such as methyl bromide, ethyl bromide, methyl chloride, propyl iodide, and the like, aralkyl halides, preferably phenyl lower alkyl halides, such as benzyl bromide, benzyl chloride, phenethyl chloride, alkyl sulfates, preferably lower alkyl sulfates such as dimethyl sulfate, diethyl sulfate, etc.

The compounds of this invention are useful as hypotensive agents, for example, for treatment of cases of hypertension. They may be administered orally or parenterally by incorporating the basic compound or pharmaceutically acceptable acid addition salt or quaternary salt with conventional carriers and/ or excipients to form tablets, capsules, injectables or the like according to conventional pharmaceutical practice.

The compounds of Formula I are produced by reacting a compound of the formula ([)H O (ll-lower alkyl C C-C wherein R=N has the same meaning as defined above and X represents a halogen preferably in an inert organic solvent such as toluene or the like, or in the presence of a metal alkanolate, e.g. an alkali metal salt or" a lower alkanol such as sodium isopropylate.

The 6,7,8,9-tetrahydro derivatives of the compounds of Formula I may be obtained by catalytically hydrogenating the latter in the presence of platinum oxide, for example.

The acid addition salts are produced by reacting the basic compound with the appropriate inorganic or organic acid. Formation of the acid salt provides a convenient method for isolating and purifying the product. Neutralization with a base such as sodium hydroxide gives the free base. Quaternary salts are produced by reaction with alkylating agents of the character described previously. Preferably an inert solvent such as methanol, dimethylformamide, acetonitrile or the like, is used.

The following examples are illustrative of this invention. Temperatures are all expressed in degrees centigrade.

EXAMPLE 1 4- (Z-Dimethylaminoethoxy -2,3,6-Trz'methoxy-5H- Benzocyclohepten-S-One To a solution of 6.9 g. of sodium in 600 ml. of isopropyl alcohol is added a slurry of 78.5 g. of 4-hydroxy-2,3,6- trimethoxy-SH-benzocyclohepten-S-one (J. Chem. Soc. 1948, 119) in 1100 ml. of hot isopropyl alcohol. The resulting mixture is stirred, heated to reflux, cooled to room temperature and treated with a solution of 43 g. of Z-dimethylaminoethyl chloride in 300 ml. of toluene. The mixture is stirred for fifteen minutes at room temperature, refluxed for three hours and'the solvent removed under reduced pressure. The residue is treated with 200 ml. of water and then 506 ml. of ether and filtered the mixture to give 29.8 g. of unreacted starting material. The filtrate layers are separated and the aqueous portion extracted three times with 300 ml. portions of ether. The ether extracts are combined and extracted with a cold solution of 25 ml. of cone. hydrochloric acid in 200 ml. of water. The aqueous layer is cooled and treated with a cold solution of 15 g. of sodium hydroxide in 40 ml.

of water. The liberated base is extracted three times with 300 ml. portions of ether. The ether extracts are combined, dried over magnesium sulfate, filtered and the solvent evaporated to give 4-(Z-dimethylaminoethoxy)- 2,3,6-trimethoxy-SH-benzocyclohepten-S-one as a pale red residue.

The residue is dissolved in 500 ml. of ether and treated with a solution of 4.3 g. of oxalic acid in 200 ml. of ether to give the oxalic acid salt as a heavy yellow precipitate, M.P. 170-175 After two crystallizations from 600 ml. portions of acetonitrile, the pale yellow product melts at 176-177 (dec.).

EXAMPLE 2 4- (Z-Diethylaminoethoxy -2,3,6-Trimethxy-5H- Benzocycloh epten-S-One By substitution of 52 g. of Z-diethylaminoethyl chlo ride for the 2-dimethylaminoethyl chloride in Example 1, there are recovered 14 g. of the starting material. The ethereal solution (1500 ml.) of the product is treated with a solution of 22 g. of oxalic acid in 500 ml. of ether to give a semi-crystalline material. After standing in the cold, the mother liquor is decanted and the semi-solid is triturated with 50 ml. of acetonitrile and filtered to give 79.5 g. of pale yellow oxalate, M.P. 131-135. After crystallization from 150 ml. of acetonitrile, the nearly colorless solid salt melts at 139-141".

EXAMPLE 3 4-(3-Dimethylaminopropoxy)-2,3,6-Trimeth0xy-5H- Benzocyclohepten-S-One By substitution of 49.0 g. of 3-dimethylaminopropyl chloride for the Z-dimethylaminoethyl chloride in Example 1, there are obtained 4-(3-dirnethylaminopropoxy)- 2,3,6-trimethoxy-SH-benzocycloheptene-S-one and its oxalic acid salt, M.P. 140-144". After crystallization from 70 ml. of acetonitrile, the pale yellow salt melts at 146 148.

EXAMPLE 4 4-(Z-DieIhyIaminoetIzoxy)-6,7,8,9-Tetrahydr0-2,3,6- T rimethoxy-5H-Benz0c3cl0hepten-5-One Oxalate A suspension of 25 g. of oxalate from Example 2 in 220 ml. of absolute alcohol is treated with 1 g. of platinum oxide and the mixture placed in a Parr apparatus under fifty-two pounds of hydrogen. Two moles of hydrogen are absorbed during eighty minutes. The mixture is filtered and the filtrate evaporated under reduced pressure to give a solid. This material is dissolved in 70 ml. of warm butanone, cooled and diluted with 70 ml. of ether to give a syrupy oil. The mother liquor is decanted and the oil triturated with ether to give 19.0 g. of colorless solid; M.P. 4550. Part of this material (17.5 g.) is suspended in 100 ml. of ethyl acetate, the solvent is decanted off and the product triturated with ether to give 4 (2 diethylaminoethoxy) 6,7,8,9 tetrahydro 2,3,6- trimethoxy-5H-benzocycloheptene-5-one oxalate as a colorless solid; M.P. 63-65 EXAMPLE 5 4 (2 -Diethylaminoethoxy 6, 7,8,9-T etrahydr0-2,3,6 -Trim ethoxy-5H-Benz0cycloh epten-S-One A suspension of 45.0 g. of material from Example 4 in 300 ml. of water is treated with a cold solution of 8 g. of sodium hydroxide in 100 ml. of water and the liberated base extracted three times With. 300 ml. portions of ether. The ether phases are combined, dried over magnesium sulfate, filtered and the filtrate evaporated leaving 34 g. of oil.

EXAMPLE 6 4-(Z-Diethylaminoelhoxy)-6,7,8,9-Tetrahydro-2,3,6-Trimethoay-SH-Benzocyclohepten-S-One Methiodide A cool solution of 18 g. of material from Example 5 in ml. of acetonitrile is treated with 18 g. of methyl iodide. After standing for eight hours at room temperature, the mixture is diluted to 500 ml. with ether to give the crystalline methiodide.

EXAMPLE 7 4- [3-(4-Methyl-l -Piperazin0)Pr0poxy]-2,3,6-Trimethoxy-5H-Benzocyclohepten-S-One By substituting 54.0 g. of 3-(4-methyl-1-piperazino) propyl chloride for 2-dimethylaminoethylchloride in the procedure of Example 1, 4-[3-(4-methyl-1-piperazino) propoxy] -2,3,6-trimethoxy-5H-benzocyclohepten 5 one and its oxalate are produced.

EXAMPLE 8 By substituting hydrochloric acid for the oxalic acid in the procedure of Example 1, the hydrochloride is produced.

EXAMPLE 9 4 (3 Isopropylaminopropoiy) 2,3,6 Triethoxy 5H- Benzocyclohepten-S-One Substitution of 42.0 of 3-isopropylaminopropyl chloride for the Z-dimethylaminoethyl chloride and 4-hydroxy-2,3, 6-triethoxy-5H-benzocyclohepten-S-one for the trimethoxy compound in Example 1 gives the base, then the orange oxalic acid salt, 4-(3-isopropylaminopropoxy)-2,3,6-triethoxy-SH-benzocyclohepten-S-one oxalate. (The benzocycloheptenone starting material is prepared by substituting diethyl sulfate for dimethyl sulfate in the procedure shown in J. Chem. Soc., 1948, page 119.)

EXAMPLE 10 4 (2 Dihydi'oxyeihylaminoethoxy) 2,3,6 Trimethoxy- 5H-Benz0cyclOhepten-S-One Substitution of 51.0 g. of Z-dihydroxyethylaminoethyl chloride for Z-dimethylaminoethyl chloride in Example 1 gives the base, then the product 4-(2-dihydroxyethylaminoethoxy) 2,3,6 trimethoxy 5H benzocyclohepten-S-one oxalate is obtained.

EXAMPLE 1 l 4 (3 Diethylaminopropoxy) 2,3,6 Trietlzoxy 5H- Benzocyclohepten-S-One Substitution of 37.0 g. of 3-diethylaminopropyl chloride for the 2-dimethylaminoethyl chloride and 4-hydroxy-2, 3,6-triethoxy-SH-benzocyclohepten-S-one for the trimethooxy compound in Example 1 gives the base, then the oxalic acid salt,

EXAMPLE 12 4 (3 Pyridylmelhoxy) 2,3,6 T rimethoxy 5H Ben- ZocycloheptenJ-One By the substitution of 39.0 of 3-pyridylmethyl chloride for the Z-dimethylaminoethyl chloride in the procedure of Example 1,4 (3 pyridylmethoxy) 2,3,6 trimethoxy- SH-benzocyclohepten-S-one and its oxalate are produced.

EXAMPLE 13 4 (3 Diethylaminopropoxy) 2,3,6 T rielhoxy 6,7,8,9 Tetrahydr0-5H-Benz0cycl0hepten-5-One What is claimed is: 1. A compound selected from the group consisting of bases of the formula R=N-lower alkylene-(l) El) O-lower alkyl C lower alkyl-OC \('3/ CH lower alky1-OC (11 (13B C C H H wherein R=N is a basic nitrogen-containing radical of less than 12 carbon atoms selected from the group consisting of amino, lower alkylamino, di-lower alkylamino, hydroxy-lower alkylamino, di-(hydIoXy-lower alkyl) amino, phenylflower alkyl)amino, N-(lower alkyD-N-(phenylfiower alkyH) amino and 5- to 6-membered monocyclic nitrogen heterocyclics. 6,7,8,9-tetrahydro derivatives, acid addition salts of said bases with pharmaceutically acceptable acids and quaternary salts of said bases with pharmaceutically acceptable quaternizing agents. 2. A compound of the formula ower alkyl N-lower alkylene? O O-lower alkyl lower alkyl lower alkyl-0-0 (I? OH lower a1ky1-0 O 4211 6 3. A compound of the formula lower alkyl N-lower alkylene? (l? OCH; loweralkyl C\ /C( J cmo-o fi \(IJH 013 0-6: 0 CH C o H H 4. 4 (2 diethylarninoethoxy) 2,3,6 trimethoxy- SH-benzocyclohepten-S-one.

dimethylaminopropoxy) 2,3,6 trimethoxy- SH-benzocyclohepten-S-one.

6. 4 (2 dimethylaminoethoxy) 2,3,6 trimet hoxy- SH-benzocyclohepten-S-one.

dimethylaminopropoxy) 2,3,6 trimethoxy- SH-benzocyclohepten-S-one oxalate.

dimethylaminoethoxy) 2,3,6 trimethoxy- SH-benzocyclohepten-S-one oxalate.

References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Horton: I. Am. Chem. Soc. vol. 77, 1955, pages 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASES OF THE FORMULA 